A. Field of the Invention
The invention relates generally to therapeutic compositions for administration to humans suffering from hepatic disorders. The described compositions in the several embodiments thereof utilize keto analogs of certain essential amino acids administered orally or parenterally, which are effective in reducing the content of ammonia in the blood stream, thereby affording symptomatic relief and reducing the toxic effects of ammonia in the circulation.
B. Description of the Prior Art
It has heretofore been proposed to employ mixtures of the essential amino acids in the treatment of uremic conditions (Bergstrom et al., U.S. Pat. No. 3,764,703). Other workers have suggested possible substitution of the corresponding keto analogs of one or more of such essential amino acids in treatment of uremic disorders, based on the assumption that such keto analogs might combine with nitrogen derived from urea breakdown in the intestines. It has subsequently been demonstrated that these assumptions were not valid. The successful treatment of renal disorders by particular compositions comprising keto analogs of certain of the essential amino acids has, however, been reported in the literature by the present applicant; see Walser, M. et al., 1973, "The Effect of Keto-analogues of Essential Amino Acids in Severe Chronic Uremia", Journal of Clinical Investigation, 52:678.
Prior to the work undertaken by the present applicant, there has been no reported clinical investigation of the use of keto analogs of amino acids in the treatment of hepatic disorders. (A footnote in the J. Clin. Invest., 50:90, speculates, without supporting data, on a potential possible application of a protein-free diet containing unnamed keto acid analogs, in the treatment of hepatic patients with ammonia intoxication, provided efficient amination or trans-amination of the keto acids could be performed in the diseased liver and/or extrahepatic tissues of these subjects). Prior art treatment of hepatic failure, such as is characterized by hyperammonemia and portal systemic encephalopathy, is generally based on attempts to reduce the production of ammonia in the intestines and to restrict dietary protein. Antibiotics are usually applied to prevent urea breakdown.
The previous attempts to reduce intestinal ammonia release in the treatment of hepatic disorders are based on the belief that the high peripheral blood ammonia present in these conditions is responsible for the symptoms of these disorders.